The Phase I project demonstrated the feasibility of developing polynitroxyl albumin (PNA) for stroke. When administered 2 hrs after transient MCA occlusion in the rat, PNA reduced mean infarct volume by 47 percent, consistent with previous mouse data. Functional MRI data indicated that PNA both improves the perfusion of the ischemic area during and after ischemia, and reduces the severity of the ischemic injury. PNA also inhibited postischemic leukocyte adhesion in the rat mesentery. These findings support a potent free radical blocking activity of PNA which attenuates ischemia/reperfusion injury. The Phase II project will extend the preclinical development of PNA, culminating in an IND submission. The project will include dose-response and toxicity testing, confirmation of efficacy in embolic stroke models. The efficacy testing will ask (1) in view of its hemodynamic effects in the ischemic brain, does PNA improve outcome when given alone in an embolic model; and (2) when given with rt-PA, does PNA improve outcome compared with rt-PA alone? The Phase II project will test the hypothesis that as a vascular agent for stroke therapy, PNA can act alone to inhibit the progression of stroke injury, and can also improve the safety and efficacy of thrombolytic therapy. PROPOSED COMMERCIAL APPLICATION: The project aims to develop PNA for stroke therapy which addresses ischemia/reperfusion injury. This may yield a drug which extend the safety and efficacy of thrombolytic therapy. The commercial potential of such an agent would be of tremendous benefit to patients and would have great commercial potential.